Journal of Medicinal Chemistry - The Consciousness Library

1-[(1-Methyl-1H-imidazol-2-yl)methyl]-4-phenylpiperidines as mGluR2 Positive Allosteric Modulators for the Treatment of Psychosis

Journal of Medicinal Chemistry March 2, 2011 Lei Zhang, Michael A. Brodney, John Candler et al. 32 citations

A new class of compounds, 1-[(1-methyl-1H-imidazol-2-yl)methyl]-4-phenylpiperidines, acts as positive allosteric modulators (PAMs) of the metabotropic glutamate receptor 2 (mGluR2). Structure-activity relationship studies produced potent and selective mGluR2 PAMs with favorable pharmacokinetic properties. The lead compound (+)-17e dose-dependently reduced methamphetamine-induced hyperactivity and mescaline-induced scratching in mice, suggesting potential for treating psychosis.

DOI: 10.1021/jm101414h Mescaline Allosteric regulation Methamphetamine Pharmacology +3

Synthesis and Pharmacological Characterization of a Series of Geometrically Constrained 5-HT2A/2C Receptor Ligands

Journal of Medicinal Chemistry July 1, 2003 James J. Chambers, Jason C. Parrish, Niels Jensen et al. 27 citations

Conformationally constrained tetrahydronaphthofurans were designed to study the optimal shape of the 2-aminoethyl moiety in phenethylamine-type serotonin 5-HT(2A) receptor agonists. In vitro assays showed that benzofuran-containing analogues (6a and 6b) had significantly higher affinity for 5-HT(1A), 5-HT(2A), and 5-HT(2C) receptors than benzodihydrofuran-containing compounds. The most potent compound, 6b, had K(i) values of 2.6 nM at 5-HT(2A) and 1.1 nM at 5-HT(2C) cloned rat receptors. Despite high affinity, these naphthofuran compounds lacked high intrinsic activity at the 5-HT(2A) receptor in the phosphoinositide hydrolysis assay. Compound 6b failed to substitute for LSD in a rat drug discrimination assay, typical for low intrinsic activity compounds. Conformational constraint produced high-affinity partial agonists, but full receptor activation requirements remain unidentified.

DOI: 10.1021/jm030064v Serotonin Stereochemistry Phenethylamine Intrinsic activity +6

Synthesis and Pharmacological Evaluation of Ring-Methylated Derivatives of 3,4-(Methylenedioxy)amphetamine (MDA)

Journal of Medicinal Chemistry February 24, 1998 Matthew Parker, Danuta Marona‐lewicka, Deborah M. Kurrasch et al. 25 citations

Adding a methyl group to the 2 or 5 position of the ring of MDA produces compounds that are more potent and more selective than MDA itself at releasing serotonin in rat brain tissue. The 2-methyl and 5-methyl derivatives were tested in rats trained to distinguish serotonin-releasing drugs from saline, confirming their activity in living animals. These compounds are among the most potent serotonin-releasing agents known and may serve as leads for developing antidepressants that work by releasing serotonin rather than blocking its reuptake.

DOI: 10.1021/jm9705925 Serotonin Methylenedioxy Pharmacology Hallucinogen +13

Stereoselective LSD-like Activity in a Series of d-Lysergic Acid Amides of (R)- and (S)-2-Aminoalkanes

Journal of Medicinal Chemistry March 1, 1995 Aaron Monte, Danuta Marona‐lewicka, Arthi Kanthasamy et al. 25 citations

Amides of d-lysergic acid with 3-pentyl, (R)- and (S)-2-pentyl, 2-hexyl, and 2-heptyl substituents were synthesized and tested for LSD-like activity. (R)-lysergamides bound more strongly than (S)-amides to 5-HT2A and 5-HT1A receptors in rat brain tissue. As the amide alkyl chain lengthened from pentyl to heptyl, (R)-isomer affinity for 5-HT2A sites decreased, while affinity for 5-HT1A peaked with (R)-2-hexyllysergamide. In rats trained to discriminate LSD from saline, (R)-alkylamides produced stronger LSD-like effects than (S)-isomers, but longer chains reduced activity, with (R)-hexylamide only partially substituting for LSD. Both isomers acted as potent 5-HT2A agonists, but (R)-pentyllysergamide stimulated phosphoinositide hydrolysis about 20 times more than the (S)-form.

DOI: 10.1021/jm00006a015 Lysergic acid diethylamide Stereochemistry Stereoselectivity Carboxamide +3

C-(4,5,6-Trimethoxyindan-1-yl)methanamine: A Mescaline Analogue Designed Using a Homology Model of the 5-HT2AReceptor

Journal of Medicinal Chemistry June 21, 2006 Thomas H. Mclean, James J. Chambers, Jason C. Parrish et al. 24 citations

A new molecule, C-(4,5,6-trimethoxyindan-1-yl)-methanamine, was designed based on a computer model of the 5-HT(2A) receptor. This compound showed three times higher affinity and potency than mescaline at the receptor, with equal efficacy. In drug discrimination tests, it fully substituted for LSD and was five times more potent than mescaline. Separating the molecule into its mirror-image forms confirmed the computer predictions: the R-(+) isomer had higher affinity and potency than the S-(-) isomer, with efficacy similar to mescaline at the 5-HT(2A) receptor.

DOI: 10.1021/jm060272y Mescaline Potency Stereochemistry Homology modeling +8

Lipophilicity and serotonin agonist activity in a series of 4-substituted mescaline analogs

Journal of Medicinal Chemistry February 1, 1977 David E. Nichols, Donald C. Dyer 23 citations

Replacing the 4-methoxy group of mescaline with larger alkyl groups or bromine increases activity at serotonin receptors in a sheep umbilical artery preparation. This increase correlates with lipophilicity, measured by 1-octanol-water partition coefficients, but activity declines when the 4-substituent reaches about five atoms in length. The findings suggest that a 3,4,5-trisubstituted pattern may be more effective than a 2,4,5-substitution pattern for receptor activity.

DOI: 10.1021/jm00212a022 Mescaline Lipophilicity Stereochemistry Serotonin agonist +2

Neoclerodanes as atypical opioid receptor ligands.

Journal of Medicinal Chemistry May 9, 2013 Thomas E Prisinzano 22 citations

Salvinorin A, the active component of the hallucinogenic plant Salvia divinorum, activates opioid receptors—the same targets as morphine—despite being non-nitrogenous, a first for opioid receptor agonists. Its effects also do not involve previously studied psychotomimetic targets. This Perspective describes a research program aimed at developing tools to understand drug tolerance and dependence, with the goal of designing new treatments for pain, drug abuse, and other central nervous system disorders.

DOI: 10.1021/jm400388u Full text Dependence Receptors Morphine Targeting +11

Substituted Naphthofurans as Hallucinogenic Phenethylamine−Ergoline Hybrid Molecules with Unexpected Muscarinic Antagonist Activity

Journal of Medicinal Chemistry May 1, 1998 Aaron Monte, Danuta Marona‐lewicka, Mechelle M. Lewis et al. 20 citations

A series of racemic naphthofurans were synthesized as hybrid molecules of phenethylamine and tryptamine/ergoline hallucinogens. Although the compounds were expected to have high affinity for serotonin 5-HT2A/2C receptors, they instead showed low affinity for those receptors and unexpected affinity for muscarinic receptors. One compound, 4d, had affinities of 12-33 nM at all muscarinic M1-M5 sites and fully antagonized carbachol at M1 and M2 receptors. The naphthofurans lacked LSD-like activity in a drug discrimination paradigm in rats, indicating that the tricyclic naphthofuran nucleus is not bioisosteric with LSD and that hallucinogenic phenethylamines cannot be directly superimposed on LSD in a common binding orientation, contrary to previous hypotheses.

DOI: 10.1021/jm980076u Serotonin Phenethylamines Muscarinic acetylcholine receptor Stereochemistry +7

Sulfur analogues of psychotomimetic agents. Monothio analogs of mescaline and isomescaline

Journal of Medicinal Chemistry November 1, 1981 Peyton Jacob, Alexander T. Shulgin 20 citations

Two sulfur-containing analogues of mescaline, 3-thiomescaline and 4-thiomescaline, were synthesized and found to be psychotomimetic in humans, with 4-thiomescaline being 12 times more potent and 3-thiomescaline 6 times more potent than mescaline itself. Three additional analogues of isomescaline were also synthesized but were not psychotomimetic. All five compounds were broken down by bovine plasma monoamine oxidase in the lab, but the rate of this enzymatic degradation did not correlate with their potency as hallucinogens in people.

DOI: 10.1021/jm00143a017 Mescaline Chemistry Psychotomimetic Pharmacology +1

What We Have Gained from Ibogaine: α3β4 Nicotinic Acetylcholine Receptor Inhibitors as Treatments for Substance Use Disorders.

Journal of Medicinal Chemistry January 12, 2023 Carolyn J Straub, Lisa E Rusali, Kyle M Kremiller et al. 19 citations

Ibogaine, the main psychoactive alkaloid in Tabernanthe iboga, has been studied for decades as a possible treatment for substance use disorders because it may interrupt addiction to multiple drugs. Its inhibition of α3β4 nicotinic acetylcholine receptors in the brain is a likely mechanism for this anti-addictive effect. This perspective examines several classes of compounds developed to target α3β4 nAChRs, focusing on those effective in pre-clinical models of drug abuse and evaluated clinically. It highlights the promising potential of α3β4 nAChRs as viable targets for treating a wide array of substance use disorders and discusses challenges that must be overcome to develop these ligands into therapeutic treatments.

DOI: 10.1021/acs.jmedchem.2c01562 Full text Ibogaine: natural compound Plant medicine Drug addiction Suds +5

Novel Psilocin Prodrugs with Altered Pharmacological Properties as Candidate Therapies for Treatment-Resistant Anxiety Disorders

Journal of Medicinal Chemistry November 20, 2023 Kaveh Matinkhoo, Lisa Yu, David Press et al. 18 citations

Psilocybin's therapeutic benefits for depression and anxiety are limited by the long duration of its psychedelic effects, driven by sustained exposure to its active metabolite psilocin. To address this, researchers synthesized and screened 28 new chemical entities, introducing various cleavable groups at the 4-hydroxy position of the indole core to alter metabolic processing. Several novel prodrugs showed altered pharmacokinetic profiles and reduced pharmacological exposure compared to psilocybin, suggesting they could maintain long-term therapeutic benefits while shortening the psychedelic experience.

DOI: 10.1021/acs.jmedchem.3c01225 Psilocybin Anxiety Prodrug Pharmacology +5

Sulfur analogs of psychotomimetic agents. 2. Analogs of (2,5-dimethoxy-4-methylphenyl)- and of (2,5-dimethoxy-4-ethylphenyl)isopropylamine

Journal of Medicinal Chemistry May 1, 1983 Peyton Jacob, Alexander T. Shulgin 18 citations

Two thio analogues of the psychotomimetic drugs DOM and DOET were synthesized and tested in humans. The 5-thio isomers are more potent than the 2-thio isomers but are about ten times less potent than the original sulfur-free drugs. The dithio analogue of DOM showed no central activity at a dose roughly 50 times the effective dose of DOM.

DOI: 10.1021/jm00359a021 Isopropylamine Psychotomimetic Thio- Tetrahydrothiophene +5

Stereoselective LSD-like activity in d-lysergic acid amides of R- and S-2-aminobutane

Journal of Medicinal Chemistry January 1, 1992 Robert Oberlender, Robert C. Pfaff, Michael P. Johnson et al. 17 citations

Both the (R)- and (S)-2-butylamides of d-lysergic acid fully substituted for LSD in rats trained to discriminate LSD from saline, and both showed very high affinity for 5-HT2 and 5-HT1A receptors. The R isomer was significantly more potent than the S isomer in both behavioral and binding assays. Molecular mechanics modeling indicated that the (R)-2-butylamide adopts a conformation similar to LSD, whereas the (S)-2-butylamide does not. These results suggest that the stereochemistry of the amide substituent critically influences hallucinogenic activity, possibly through stereoselective interactions with a hydrophobic receptor region or by inducing conformational changes elsewhere in the molecule.

DOI: 10.1021/jm00080a001 Lysergic acid diethylamide Stereochemistry Agonist Substituent +4

Bufotenine esters.

Journal of Medicinal Chemistry November 1, 1979 R A Glennon, P K Gessner, D D Godse et al. 17 citations

Bufotenine, a psychoactive compound, has weak behavioral effects in humans and animals, likely because it cannot easily cross the blood-brain barrier. Researchers synthesized several ester derivatives of bufotenine to evaluate them pharmacologically. Unexpectedly, all the esters showed strong affinity for serotonin receptors in isolated rat stomach tissue. Chromatographic analysis indicated that the esters were not extensively broken down into bufotenine during the assay, suggesting the esters themselves may be active at these receptors.

DOI: 10.1021/jm00197a025 Full text

Resolution and absolute configuration of trans-2-(2,5-dimethoxy-4-methylphenyl)cyclopropylamine, a potent hallucinogen analog

Journal of Medicinal Chemistry April 1, 1979 David E. Nichols, Ronald W. Woodard, Bruce A. Hathaway et al. 16 citations

The hallucinogen analogue DMCPA was separated into its two mirror-image forms using a crystallization technique. By comparing the optical properties of these forms to a related compound of known structure, the absolute configuration of the (-) isomer was determined to be (1R,2S) and the (+) isomer (1S,2R). Earlier work showed the (-) isomer causes selective behavioral effects in cats and mice; this study found it also selectively raises body temperature in rabbits compared to the (+) isomer. This stereoselective activity supports a model linking the active binding conformation of phenethylamine hallucinogens to that of serotonin and tryptamines.

DOI: 10.1021/jm00190a021 Citation Altmetrics Computer science Icon +3

Further Studies on Oxygenated Tryptamines with LSD-like Activity Incorporating a Chiral Pyrrolidine Moiety into the Side Chain

Journal of Medicinal Chemistry September 16, 1999 Madina R. Gerasimov, Danuta Marona‐lewicka, Deborah Kurrasch‐orbaugh et al. 15 citations

The R enantiomers of two rigid tryptamine analogues show a 10-20-fold higher affinity for the 5-HT(2A) receptor than the S enantiomers, with no distinction based on the position of the oxygen group. The R enantiomers of both compounds have nearly identical affinities at the agonist-labeled receptor, while racemic versions of related compounds have about one-tenth the affinity. In rats trained to discriminate LSD or DOI from saline, the R enantiomers are about equipotent to DOI but about 10-fold less potent than LSD. One compound produced only partial substitution even at a dose nearly 5-fold higher than for the active R enantiomer. The results suggest these compounds would possess LSD-like psychopharmacology in humans.

DOI: 10.1021/jm990325u Enantiomer Stereochemistry Tryptamine Ligand biochemistry +7

Sulfur analogs of psychotomimetic agents. 30. Ethyl homologs of mescaline and their monothioanalogs

Journal of Medicinal Chemistry July 1, 1984 Peyton Jacob, Alexander T. Shulgin 14 citations

All possible monothio analogues of mono-, di-, and triethoxy homologues of mescaline were synthesized and tested in humans. Modifications at the ring position para to the ethylamine chain, using a sulfur atom, a longer alkyl chain, or both, produce compounds with high central nervous system activity. The 4-n-propoxy and 4-n-butoxy homologues and their corresponding 4-thio analogues were also made and tested. Propyl homologues retain high potency, but a butyl group, with or without sulfur, reduces activity. Meta-ethyl or meta-thio analogues retain some central action, while diethoxy and especially triethoxy homologues are relatively inactive as psychotomimetic drugs.

DOI: 10.1021/jm00373a013 Mescaline Psychotomimetic Citation Social media +4

Synthesis of Phenethylamines Related to Mescaline as Possible Psychotomimetic Agents1

Journal of Medicinal Chemistry May 1, 1963 Orrie M. Friedman, Krishnan Parameswaran, Sumner Burstein 14 citations

Several new phenethylamine compounds structurally related to mescaline were synthesized and tested for psychotomimetic activity in animals. The synthesis involved introducing sulfur and phosphorus substituents into the phenethylamine backbone. Some of the new compounds produced behavioral effects in animals similar to those of mescaline, suggesting they may act as hallucinogens. The work aimed to explore how chemical modifications to the mescaline structure affect psychoactive potency.

DOI: 10.1021/jm00339a002 Mescaline Phenethylamines Chemistry Psychotomimetic +2

Chemical and enzymatic oxidative coupling of 5-hydroxy-N,N-dimethyltryptamine with amines.

Journal of Medicinal Chemistry July 1, 1987 F Babin, T Huynh-Dinh 13 citations

An oxidative coupling method was developed to covalently label serotonin receptors. Oxidizing bufotenine with MnO2 or human ceruloplasmin, then adding dansylcadaverine or dansyllysine, produced a fluorescent adduct with a fused oxazole structure. This approach offers a way to attach fluorescent tags to serotonin derivatives for studying receptor binding.

DOI: 10.1021/jm00390a020 Full text

Phenylalkylamines with potential psychotherapeutic utility. 2. Nuclear substituted 2-amino-1-phenylbutanes

Journal of Medicinal Chemistry February 1, 1980 Robert T. Standridge, Henry G. Howell, Hugh A. Tilson et al. 13 citations

A series of new chemical compounds similar to a known hallucinogen were synthesized and tested in animals. Most of the analogues showed low hallucinogenic potential. The compounds were compared with a reference substance in a behavioral model that distinguishes hallucinogenic from non-hallucinogenic drugs. The chemical structures and their effects are discussed.

DOI: 10.1021/jm00176a010 Hallucinogen Butane Stereochemistry Chemical synthesis +2

Synthesis and evaluation of substituted 2-phenylcyclobutylamines as analogs of hallucinogenic phenethylamines: lack of LSD-like biological activity

Journal of Medicinal Chemistry September 1, 1984 David E. Nichols, K. P. Jadhav, Robert Oberlender et al. 12 citations

Three new compounds—cis- and trans-2-(2,4,5-trimethoxyphenyl)cyclobutylamine and trans-2-(2,5-dimethoxy-4-methylphenyl)cyclobutylamine—were synthesized as rigid versions of hallucinogenic phenylisopropylamines. In rats trained to distinguish LSD from saline, the cis compound did not produce LSD-like effects at doses up to 20 mg/kg. Both trans compounds partially mimicked LSD at 5 mg/kg or higher. In contrast, a related cyclopropylamine compound fully substituted for LSD. The trans cyclobutylamines were about 50 to 75 times less potent than the cyclopropylamine analogue. The lack of full generalization suggests these cyclobutylamines either produce different effects from LSD or lack discriminative effects entirely.

DOI: 10.1021/jm00375a004 Mescaline Phenethylamines Hallucinogen Biological activity +2

Discovery and Structure–Activity Relationships of 2,5-Dimethoxyphenylpiperidines as Selective Serotonin 5-HT2A Receptor Agonists

Journal of Medicinal Chemistry April 22, 2024 Karla Frydenvang, Emil Märcher-Rørsted, Anders A. Jensen et al. 7 citations

Classical psychedelics like psilocybin, LSD, and DMT show promise for treating depression, anxiety, and substance abuse, but their long-term therapeutic effects remain unclear. A new class of compounds, 2,5-dimethoxyphenylpiperidines, has been discovered as selective serotonin 2A receptor (5-HT2AR) agonists. Structure-activity studies identified LPH-5 [analogue (S)-11] as a selective 5-HT2AR agonist with favorable drug-like properties, offering a potential tool to investigate the receptor's role in persistent therapeutic effects.

DOI: 10.1021/acs.jmedchem.4c00082 Pharmacology 5-HT Receptor Structure–activity relationship Serotonin agonist +1

Structural Basis for Molecular Recognition of Cannabinoids by Inhibitory Cys-Loop Channels.

Journal of Medicinal Chemistry March 14, 2024 Lautaro D Alvarez, N R Carina Alves 7 citations

Cannabinoids from Cannabis sativa interact with human proteins called Cys-loop receptors, which mediate inhibitory signals in the nervous system. The binding sites for cannabinoids on these receptors are located within the transmembrane domain, but their exact positions have remained unknown for over a decade. This Perspective describes the computational methods used to identify these binding sites, including analysis of recently resolved cryo-EM structures of zebrafish glycine receptors bound to Δ9-tetrahydrocannabinol and molecular dynamics simulations of the THC-GlyR complex. The work aims to guide future studies on the molecular basis of cannabinoid action on inhibitory channels.

DOI: 10.1021/acs.jmedchem.3c02391 Full text

Isomeric cyclopropyl ring-methylated homologs of trans-2-(2,5-dimethoxy-4-methylphenyl)cyclopropylamine, an hallucinogen analog

Journal of Medicinal Chemistry May 1, 1982 James N. Jacob, David E. Nichols 6 citations

Adding a methyl group at the 3-position of the cyclopropyl ring, in either the cis or trans orientation relative to the amino group, eliminated the activity of the hallucinogen analogue trans-2-(2,5-dimethoxy-4-methylphenyl)cyclopropylamine. Neither the cis nor the trans isomer showed appreciable activity in the mouse ear-scratch assay or in producing contraction in the rat fundus preparation, compared to the nonmethylated parent compound.

DOI: 10.1021/jm00347a009 Hallucinogen Stereochemistry Ring chemistry Pharmacology +2

Identification of Psychoplastogenic Tropanes Lacking Muscarinic Activity

Journal of Medicinal Chemistry July 9, 2024 Hunter T Warren, Winston L. Chow, Milan Chytil et al. 5 citations

Tropane-containing small molecules such as scopolamine can promote neuronal growth (psychoplastogens) but also block all muscarinic receptor subtypes, causing unwanted anticholinergic side effects. Researchers conducted phenotypic structure-activity relationship studies on various tropane subclasses to separate these effects. They identified several novel tropanes that substantially increase cortical neuron growth while showing much weaker activity at all muscarinic receptor subtypes than scopolamine, suggesting that the neuroplasticity-promoting and muscarinic-blocking properties can be decoupled.

DOI: 10.1021/acs.jmedchem.4c01204 Muscarinic acetylcholine receptor Identification biology Pharmacology Biochemistry +1

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